Aging impairs flow-induced dilation in coronary arterioles: role of NO and H₂O₂

Abstract

The beneficial effects of nitric oxide (NO)-mediated vasodilation are quickly abolished in the presence of ROS, and this effect may be augmented with aging. We previously demonstrated an age-induced impairment of flow-induced dilation in rat coronary arterioles. Therefore, the purpose of this study was to determine the effects of O 2 Ϫ scavenging, as well as removal of H2O2, the byproduct of O 2 Ϫ scavenging, on flow-mediated dilation in coronary resistance arterioles of young (4 mo) and old (24 mo) male Fischer 344 rats. Flow increased NO and H 2O2 production as evidenced by enhanced diaminofluorescein and dichlorodihydrofluorescein fluorescence, respectively, whereas aging reduced flow-induced NO and H 2O2 production. Endothelium-dependent vasodilation was evaluated by increasing intraluminal flow (5-60 nl/s) before and after treatment with the superoxide dismutase mimetic Tempol (100 M), the H 2O2 scavenger catalase (100 U/ml), or Tempol plus catalase. Catalase reduced flowinduced dilation in both groups, whereas Tempol and Tempol plus catalase diminished vasodilation in young but not old rats. Tempol plus deferoxamine (100 M), an inhibitor of hydroxyl radical formation, reversed Tempol-mediated impairment of flow-induced vasodilation in young rats and improved flow-induced vasodilation in old rats compared with control. Immunoblot analysis revealed increases in endogenous superoxide dismutase, catalase, and nitrotyrosine protein levels with aging. Collectively, these data indicate that NO-and H 2O2-mediated flow-induced signaling decline with age in coronary arterioles and that elevated hydroxyl radical formation contributes to the age-related impairment of flow-induced vasodilation.reactive oxygen species; superoxide dismutase; hydroxyl radical; deferoxamine; nitric oxide; hydrogen peroxide INCREASING EVIDENCE INDICATES that aging contributes significantly to the development of ischemic heart disease. Vascular resistance increases, leading to impairments in coronary blood flow and flow reserve (15). Endothelial dysfunction similarly progresses with aging (4) and may be mediated by impaired nitric oxide (NO) activity (7, 21) or elevated oxidant stress (6, 10). Previous studies have demonstrated age-associated declines in flow-mediated dilation in coronary arterioles due to impaired phosphatidylinositol 3-kinase signaling (21) or elevated superoxide (O 2 Ϫ ) production (7). Because flow-induced vasodilation is inextricably linked to NO-mediated signaling, it is possible that other factors directly involved in the NO pathway may be altered with advancing age.In (6,7,12). Thus ROS production and scavenging are likely carefully modulated to produce appropriate flow-induced dilation. Therefore, the purpose of our study was 1) to investigate age-related changes in NO and H 2 O 2 signaling during flow-induced vasodilation and 2) to examine the effects of ROS scavenging on flow-mediated dilation in coronary arterioles. METHODSAnimals. All procedures in this study were approved by the Institutional Animal Care and U...

Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles

“…5). These data contrast our findings in coronary arterioles from male rats, where a reduction of H 2 O 2 signaling contributes to age-induced impairment of flow-induced vasodilation (21). In vessels from wild-type and ER␤ knockout male mice, catalase induced similar impairment of endothelium-mediated vasodilation (26).…”

“…Furthermore, elevated hydroxyl radical formation contributes to impairment of flowinduced vasodilation in coronary arterioles from aged male rats (21). Although we have reported an age-related reduction in flow-induced, NO-mediated vasodilation in coronary resistance vessels from female rats (23), the contribution of oxidant stress to this loss of NO-mediated dilation has not been determined.…”

“…We have previously demonstrated an age-induced impairment of flowinduced, NO-mediated dilation in coronary arterioles from male and female rats (24,26). In coronary arterioles from aged male rats, an imbalance in antioxidant defense mechanisms contributes to reduced NO availability (21); however, despite the known antioxidant effects of estrogen (7,43), the impact of estrogen on reactive oxygen species (ROS) and regulation of NO signaling in the coronary resistance vasculature of aging females remains poorly understood.…”

Effects of short-term dietary nitrate supplementation on blood pressure, O2uptake kinetics, and muscle and cognitive function in older adults

“…In addition, superoxide (O 2 Ϫ ) production is increased with aging, which would also be expected to lower NO bioavailability, given the rapid reaction between (O 2 Ϫ ) and NO to form peroxynitrite (37). Given the positive association between NO and vascular health (34), these agingrelated perturbations to NO metabolism might contribute toward the endothelial dysfunction (46,52) and arterial hypertension (26) that develop with old age.…”

The Aging Heart and Estrogen

“…Similarly, flow-mediated dilation, which is a very important physiologic response, is altered with aging and estrogen loss. Both ovx and aging attenuated flowinduced, arteriole dilation, and this was reversed in young Fischer 344 rats by E2 replacement [18]. In aged rats, flow-induced dilation was impaired in ovx and intact rats, but both had improvement with E2 replacement, likely reflecting the reduction in E2 levels in the aged rats [19].…”